Alterations and Their Clinical Significance in Cholangiocarcinoma

Background: ARID1A is a member of the SWI/SNF chromatin remodeling complex. It functions as a tumor suppressor and several therapeutic targets in -mutated cancers are currently under development, including EZH2. A synthetic lethal relationship between ARID1A and EZH2 has been revealed in several tumor entities. Although genomic alterations of have been described in various cancers, no study has examined correlations between gene mutation and protein expression with clinicopathologic parameters and prognosis, particularly in liver fluke-related cholangiocarcinoma (Ov-CCA). Here, we investigated the clinical significance of mutations and protein expression in CCA tissues and determined whether there is a correlation with EZH2 protein expression.

Methods: We evaluated ARID1A and EZH2 immunoreactivity using immunohistochemistry in 98 Ov-CCA with a wide range of clinicopathological features. Somatic mutations of were analyzed using the ICGC sequencing data in 489 of Ov and non Ov-CCA and assessed prognostic values.

Results: While detecting a loss or reduction of ARID1A expression in 54 cases (55%) in Ov-CCA, ARID1A expression was associated with mutations ( < 0.001, adjusted -value < 0.001). We observed that 12 of 13 tumors (92%) with loss of ARID1A expression had truncating mutations. There were nine of 13 tumors (69%) with loss of ARID1A expression and 25 of 41 tumors (61%) with low ARID1A expression exhibited distant metastasis ( = 0.028, adjusted -value = 0.168). was predominantly mutated in Ov-CCA compared to non Ov-CCA (24% and 14% in Ov-CCA and non Ov-CCA, respectively, = 0.027). There were 36 of 72 (50%) and 52 of 79 (66%) tumors with mutation showed tumor stage IV and T3/T4, respectively. The significant mutual exclusivity and co-occurrence between and mutations were not found in ICGC cohort. In addition, high EZH2 expression, a potential synthetic lethal target in -mutated tumors, was detected in 49 of 98 Ov-CCA (50%). Importantly, neither ARID1A expression nor mutations correlated with EZH2 expression in this cohort.

Conclusion: We found that inactivation, by somatic mutation or by loss of expression, frequently occurs in Ov-CCA. Reduction of ARID1A expression and/or somatic mutation was shown to be associated with CCA progression. These findings suggest that ARID1A may serve as a prognostic biomarker, and thus may be a promising therapeutic target for CCA.